Pleiotropic Role Played by the PDZ Domain in Neuronal Signaling Pathways

Abstract

The human tyrosine phosphatase PTPN4 and the Ser/Thr kinase MAST2 are two enzymes expressed in neurons. While PTPN4 is an anti-apoptotic protein, MAST2 inhibits neurogenesis and neuroprotection. The PDZ domain of these two enzymes is specifically targeted by the glycoprotein of the rabies virus during neuron infection. We have solved the NMR and X-ray structures of the complexes formed by MAST2-PDZ and PTPN4-PDZ with their respectives endogenous and viral ligands. As a result, the complexes formed by the PDZ of the two enzymes and their respective ligands are disrupted, triggering drastic effect on cell signaling and cell commitment either towards death or survival. The glycoprotein disrupts the interactions of MAST2 and PTPN4 PDZ domains with their respective cellular ligands, the phosphatase PTEN and the MAP kinase p38γ.The PDZ domains of MAST2 and PTPN4 contribute to the recruitment of substrates but also to the catalytic regulation modulating the phosphorylation/dephosphorylation of endogenous partners. On the one hand, the binding of PTEN to the PDZ domain of MAST2 prevents MAST2 auto-association and drastically increases the phosphorylation level of PTEN. We identified by NMR two independent cascades of PTEN phosphorylation, in vitro and in cell extracts, that could activate different regulatory responses of the phosphatase. On the other hand, we combine X-ray crystallography, SAXS and NMR, to show that the PDZ domain of PTPN4 inhibits the catalytic activity of the flanking phosphatase domain and the mere binding of the p38γ PDZ binding sequence is sufficient to allosterically restore the catalytic competence of PTPN4 by disrupting the inter-domain communication.Caillet-Saguy et al. (2015) Prog Biophys Mol Biol. 119(1):53-9.Delhommel F et al. (2015) Biochemical Journal 469(1) :159-168.Vincentelli R et al. (2015) Nature Methods 8 :787-793.Cordier, F.,et al.(2015) Methods, 77-78:82-91.